Focal Segmental Glomerulosclerosis (FSGS) is a heterogeneous and devastating disease that is one of the major causes of renal failure. The long-term goals of the proposed research are to provide a deeper understanding of this disease, to identify novel therapeutic targets that might lead to more effective treatments, and to define gene expression signature based subtypes that are useful guides for therapy. Towards these ends we propose the following specific aims. Specific Aim 1. Define the normal gene expression patterns of the glomerulus, and its cellular constituents, the podocyte, the mesangial cell and the endothelial cell. The results will reveal the molecular pathways active in each of these very interesting cells. We propose to use laser capture microdissection (LCM), as well as transgenic mice with cell specific reporter expression and fluorescent activated cell sorting, to isolate glomeruli and its three cell type components. Microarrays will then be used to profile precise gene expression patterns. Specific Aim 2. We also propose to use four mouse models of glomerulosclerosis to define the altered gene expression states and functional pathways resulting from four distinct initiating insults, one chemical and three genetic. This will create a detailed molecular picture of the progression of glomerulosclerosis and test the common final pathway hypothesis, which states that regardless of initial cause there are important shared aspects in the resulting glomerulosclerosis. Specific Aim 3. To define the altered functional pathways of the Human FSGS glomerulus. By using LCM and microarrays it will be possible to define the changes in gene expression that occur in the diseased glomerulus. By examining many glomeruli, from fifty patients, it will be possible to begin to understand the underlying molecular causes of the observed glomerulosclerosis, to subtype this heterogeneous disease based on gene expression signatures, to compare gene expression patterns as a function of disease progression, and to correlate gene expression markers with therapeutic response. For most FSGS patients there is currently no effective therapy, and kidney failure is the end result. We propose to use a combination of cutting edge technologies to study the normal glomerulus as well as the diseased glomerulus, in both humans and well- defined mouse models, to better understand this disease and to help discover improved methods of treatment. PUBLIC HEALTH RELEVANCE: For most FSGS patients there is currently no effective therapy, and kidney failure is the end result. We propose to use a combination of cutting edge technologies to study the normal glomerulus as well as the diseased glomerulus, in both humans and well- defined mouse models, to better understand this disease and to help discover improved methods of treatment.